The present invention relates to a method for the preparation of the well known anti-depressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.
Citalopram is a well known antidepressant drug that has now been on the market for some years and has the following structure: 
It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, eg. J. Hyttel, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486. The compound has further been disclosed to show effects in the treatment of dementia and cerebrovascular disorders, EP-A 474580.
Citalopram was first disclosed in DE 2,657,271, corresponding to U.S. Pat. No. 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method which may be used for preparing citalopram.
According to the process described, the corresponding 1-(4-fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile is reacted with 3-(N,N-dimethylamino)propyl-chloride in the presence of methylsulfinylmethide as condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide. According to the method, which is only outlined in general terms, citalopram may be obtained by ring closure of the compound: 
in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cuprous cyanide. The starting material of Formula 11 is obtained from 5-bromophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium chloride and N,N-dimethylaminopropyl magnesium chloride, respectively.
A new and surprising method and an intermediate for the preparation of citalopram were described in U.S. Pat. No. 4,650,884 according to which an intermediate of the formula 
is subjected to a ring closure reaction by dehydration with strong sulfuric acid in order to obtain citalopram. The intermediate of Formula III was prepared from 5-cyanophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively.
Further processes are disclosed in International patent application Nos. WO 98019511, WO 98019512 and WO 98019513. WO 98019512 and WO 98019513 relate to methods wherein a 5-amino-, 5-carboxy- or 5-(sec. aminocarbonyl)phthalide is subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e. citalopram. International patent application No. WO 98019511 discloses a process for the manufacture of citalopram wherein a (4-substituted-2-hydroxymethylphenyl-(4-fluorophenyl)methanol compound is subjected to ring closure and the resulting 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran converted to the corresponding 5-cyano derivative which is alkylated with a (3-dimethylamino)propylhalogenide in order to obtain citalopram.
Finally, methods of preparing the individual enantiomers of citalopram are disclosed in U.S. Pat. No. 4,943,590 from which it also appears that the ring closure of the intermediate of Formula III may be carried out via a labile ester with a base.
It has now, surprisingly, been found that citalopram may be manufactured by a novel favourable and safe procedure using convenient starting materials.
Accordingly, the present invention relates to a novel method for the preparation of citalopram comprising reaction of a compound of Formula IV 
wherein R is C1-6 alkyl, acyl, C1-6 alkylsulfonyl or arylsulfonyl, with 3-(N, N-dimethylamino)-propyl magnesium halide, preferably of 3-(N,N-dimethylamino)propyl magnesium chloride to afford citalopram 
which is isolated as the base or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides the novel intermediates of Formula IV.
In a further aspect, the invention relates to methods for preparing the intermediates of Formula IV.
In yet another aspect of the invention, the compounds of Formula IV are used for the preparation of the racemic compound of Formula III. 
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram manufactured by the process of the invention.
By the process of the invention, citalopram is obtained by a single step Grignard reaction from the compounds of Formula IV, wherein R is C1-6 alkyl, acyl, C1-6 alkylsulfonyl or arylsulfonyl 
Surprisingly, the product of the Grignard reaction ring closes spontaneously and directly to citalopram, and accordingly the reaction of compound of Formula IV with the Grignard reagent leads to citalopram in one step.
Furthermore, according to the invention the compounds of Formula IV may be prepared by three different methods.
One of these methods includes protection of the hydroxymethylalcohol of (4-cyano-2-hydroxymethylphenyl)(4-fluorophenyl)methanol of Formula VI: 
followed by an oxidation to afford the compounds of Formula IV, wherein R is C1-6 alkyl, acyl, C1-6 alkylsulfonyl or arylsulfonyl.
The oxidation of the compounds of Formula V, may be performed by any convenient oxidation agent, preferably performed by Na2WO4.
The starting material of the compound of Formula VI may be prepared as described in International Patent Application No. PCT/DK97/00511.
Another method for preparing the compounds of Formula IV includes the reaction of 5-cyanophthalide with 4-fluorophenylmagnesiumhalide, preferably 4-fluorophenyl-magnesiumbromide followed by the reaction with R-X, wherein R is as defined above and X is a leaving group, preferably R-X is pivaloylchloride, 3,5-dimethoxybenzoylchloride, methyliodide, ethylbromide, tosyichloride, Me2SO4 or MeSO2Cl.
The reaction is illustrated below: 
The starting material, 5-cyanophthalide, may be prepared as described in Tirouflet, J.; Bull.Soc.Sci. Bretagne 26, 1959,35.
According to the third method for preparing the compound of Formula IV, one of the enantiomers of the compound of Formula III, i.e. the R-enantiomer, is subjected to protection and dehydration to give the compound of Formula VII, which is oxidised to give the ketone of Formula IV. 
In this way, the R-enantiomer of Formula III may be used in the preparation of racemic citalopram.
The oxidative cleavage of the compound of Formula VII is effected by oxidation, preferably performed by MnO4xe2x88x92 (permanganates), or ozone, RuCl3, OsO4.
Citalopram is on the market as an antidepressant drug in the form of the racemate. However, in the near future the active S-enantiomer of citalopram is also going to be introduced to the market.
The active S-enantiomer of citalopram may be prepared from the compound of Formula III by separation of the S-enantiomer and the R-enantiomer followed by ring closure of the S-enantiomer as described in U.S. Pat. No. 4,943,590. The R-enantiomer of the compound of Formula III has previously not been used after separation.
Furthermore, according to a further aspect of the invention, after conversion of the R-enantiomer of Formula III to the non-optically active compound of Formula IV, the racemic compound of Formula III may be prepared as illustrated below: 
The racemic compound of Formula III may be separated into the optically active enantiomers by the procedure described in U.S. Pat. No. 4,943,590 thereby obtaining the S-enantiomer of the compound of Formula III, which is used in the preparation of S-citalopram. The R-enantiomer of the compound of Formula III can be recycled once more in the process cycle described above.
In this way, the R-enantiomer of Formula III may be converted to S-citalopram.
Other reaction conditions, solvents, etc. for the reactions described above are conventional conditions for such reactions and may easily be determined by a person skilled in the art.
Throughout the specification and claims, the term C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.
The term aryl refers to a mono- or bicyclic carbocyclic aromatic group, such as phenyl and naphthyl, in particular phenyl or ring substituted phenyl.
The term heteroaryl refers to a mono- or bicyclic heterocyclic aromatic group, such as indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl, and furanyl, in particular pyrimidyl, indolyl, and thienyl.
Acyl is used in the meaning of C1-6 alkyl- or aryl- or heteroarylcarbonyl wherein C1-6 alkyl and aryl and heteroaryl are as defined above.
Halogen means chloro, bromo or iodo.
Preferably leaving group means halogenide or sulphonate.
In a preferred embodiment of the invention, R is acyl, preferably pivaloyl, acetyl or optionally substituted benzoyl.
The compound of general Formula I may be used as the free base or as a pharmaceutically acceptable acid addition salt thereof. As acid addition salts, such salts formed with organic or inorganic acids may be used. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-arninobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
The acid addition salts of the compounds may be prepared by methods known in the art. The base is reacted with either the calculated amount of acid in a water miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooling, or with an excess of the acid in a water immiscible solvent, such as ethylether, ethylacetate or dichloromethane, with the salt separating spontaneously.
The pharmaceutical compositions of the invention may be administered in any suitable way and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of usual sterile solutions for injection.
The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive colourings, aroma, preservatives etc. may be used provided that they are compatible with the active ingredients.
Solutions for injections may be prepared by solving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilisation of the solution and filling in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.